Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 beta 1-adrenoceptors versus Gly389 beta 1-adrenoceptors in isolated human atrial myocardium

Br J Pharmacol. 2003 Jan;138(2):386-92. doi: 10.1038/sj.bjp.0705030.


1. We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R beta(1)-adrenoceptor polymorphism. 2. Right atrial appendage was obtained from homozygous RR patients (n=37) and homozygous GG patients (n=17) undergoing elective cardiac surgery. The positive inotropic effect of noradrenaline in these tissues, mediated through beta(1)-adrenoceptors, was studied using electrically stimulated (1 Hz) atrial strips, as well as the effects of noradrenaline on cyclic AMP levels and cyclic AMP-dependent protein kinase. 3. Tissue from RR homozygotes (n=14) showed significantly increased inotropic potency to noradrenaline (-log EC(50), M=6.92+/-0.12) compared to GG homozygotes (n=8, -log EC(50), M=6.36+/-0.11, P<0.005). This difference was not dependent on tissue basal force. 4. Tissue cyclic AMP levels (pmol mg(-1)) were also greater in RR homozygotes (basal 34.8+/-3.7 n=12, 300 nM noradrenaline 41.4+/-7.6 n=9, 30 micro M noradrenaline 45.2+/-3.2 n=22, 0.2 mM isoprenaline 48.3+/-4.2 n=16) compared to GG homozygotes (basal 30.7+/-4.4 n=5, 300 nM noradrenaline 32.6+/-6.92 n=5, 30 micro M noradrenaline 38.1+/-3.1 n=8, 0.2 mM isoprenaline 42.6+/-5.2 n=6, P=0.007). There were no differences between the variants in terms of cyclic AMP-dependent protein kinase activity. 5. These data provide the first evidence that enhanced G-protein coupling of the R389 beta(1)-adrenoceptor variant reported in rodent fibroblast expression systems is also present in native human receptors. The functional consequence of this is to significantly alter the inotropic potency of beta(1)-adrenoceptor activation depending on its genotype at the 389 position.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Agonists
  • Aged
  • Analysis of Variance
  • Arginine* / genetics
  • Arginine* / metabolism
  • Cyclic AMP / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Genetic Variation / drug effects
  • Genetic Variation / physiology
  • Genotype
  • Glycine* / genetics
  • Glycine* / metabolism
  • Heart Atria / drug effects
  • Heart Atria / metabolism
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects*
  • Myocardial Contraction / physiology
  • Myocardium / metabolism*
  • Norepinephrine / pharmacology*
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-1 / physiology*
  • Stimulation, Chemical


  • Adrenergic beta-1 Receptor Agonists
  • Receptors, Adrenergic, beta-1
  • Arginine
  • Cyclic AMP
  • Glycine
  • Norepinephrine